Chimeric Antigen Receptor (CAR) T Cell Therapy For Solid Tumors

Projektinformationen

CAR-T-uning

ID Finanzhilfevereinbarung: 101054365

DOI

10.3030/101054365

Projekt abgeschlossen

EK-Unterschriftsdatum 8 Juli 2022

Startdatum 1 September 2022

Enddatum 29 Februar 2024

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 150 000,00

Koordiniert durch

MEDIZINISCHE UNIVERSITAT INNSBRUCK
Austria

Periodic Reporting for period 1 - CAR-T-uning (Chimeric Antigen Receptor (CAR) T Cell Therapy For Solid Tumors)

Berichtszeitraum: 2022-09-01 bis 2024-02-29

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Our research has provided valuable preclinical information on the enhanced therapeutic efficacy of NR2F6 gene-modified CAR-T cell therapies also for solid tumors.
Indeed, the present ERC PoC 'CAR-T-uning' project research has validated the use of NR2F6-modified CAR-T, which has the promising key property of reducing any systemic on-target/off-tumor toxicity as well as irAE by a solid tumor-targeted CAR-T cell therapy regimen.
In addition, by reducing the need for repeated treatments, it has the potential to reduce patient suffering and the cost of therapy.
The host institute MUI and the PI Univ.-Prof. Gottfried Baier and his team are the owner of the detailed validation data. It will be disclosed in publications after an appropriate embargo period required for intellectual property protection.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Within immunotherapies, CAR-T cell therapies are an advancing technology that has gained recognition over the past decade.
The approved CAR-T cell therapy currently on the market are all 1) targeting cancer of liquid tissues and 2) based on autologous cells (i.e. the cells are obtained from the patients).
Despite the active research field, a breakthrough for solid cancer still has to be found.
The proprietary novel approach of CAR-T-uning, as developed in our given PoC project, is based on gene editing of a T cell inhibitor established by the Prof. Baier team, NR2F6, which results in a potent trigger of CAR-T therapy benefits.
NR2F6 is a distantly related member of the nuclear receptor family with a long history of successful drug discovery.
Milieu signals in the tumor immune microenvironment (TIME) cause a highly localised NR2F6 upregulation in resident tumour T cells. This is because NR2F6 has an inhibitory effect on T cells' activity that fosters tumor immune escape within the TIME.
Our approach involves CAR-T therapy using a CRISPR(Cas9) sgRNA/RNP transfection method that depletes NR2F6, thereby sensitising the CAR-T cells to improve their anti-tumor activity and response rate to therapy.
Mechanistically, NR2F6-modified CAR-T cells are more effective at killing cancer cells bearing the CAR-targeted antigen.
Taken together, NR2F6 is an intrinsic T lymphocyte factor that acts as an inducible intracellular cancer immune checkpoint and drives primary and acquired resistance to immunotherapy in solid tumors, leading to tumor progression.
Therefore, NR2F6-modified CAR-T plug-in technology appears as a unique therapy option for solid tumors.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Professor Baier's group has developed a safe, effective and potentially curative CAR-T therapy for the treatment of solid tumors such as non-small cell lung cancer (see figure below).
In the future, this CAR-T approach will involve the inhibition of NR2F6 (nuclear receptor subfamily 2, group F, member 6) function in autologous T cells derived from the patient's PBMC.
This inhibition allows the delivery of a CAR-T cell product with greatly enhanced T-cell fitness, enabling the infused CAR-T cells to better overcome the immunosuppression of the TIME and robustly mitigate tumor progression.
Therefore, further development of the NR2F6-modified CAR-T infusion technology could ultimately be of significant clinical value.

car-t-uning-moa-concept.jpeg